This invention relates to 3-bicycloindole compounds, to pharmaceutical and diagnostic compositions containing them and to their medical use, particularly in the treatment or diagnosis of CNS conditions.
Through its interaction with receptors borne on neuronal and other cells, 5-hydroxytryptamine (5-HT or serotonin) exerts various physiological effects. Imbalances in this interaction are believed to be responsible for such conditions as anxiety, hallucination, migraine, chemotherapy-induced nausea and for disorders in sexual activity, cardiovascular activity and thermoregulation, among others. From an improved understanding of the 5-HT receptor population, it is apparent that these effects are mediated selectively through individual types and subtypes of the 5-HT receptors. Migraine, for example, has been treated with ergotamine, dihydroergotamine, methylsergide and, most recently, sumatriptan, all of which presumably act at 5-HT1D receptor subtype.
Current treatments for migraine, including sumatriptan, continue to have unwanted side effects. These include coronary vasospasm, hypertension and angina. Recent evidence suggests that sumatriptan""s contraction of coronary arteries may be mediated by its stimulation of the 5-HT1B (formerly 5-HT1Dxcex2) subtype of the 5-HT receptors (Kaumann, A. J. Circulation, 1994, 90:1141-1153).
Given the physiological and clinical significance of the 5-HT1D receptor, and the potential side effect liability of stimulation of its 5-HT1B receptor, it would be desirable to provide compounds that bind with high affinity to the 5-HT1D receptor. Such compounds would be medically useful, for example, to treat indications such as migraine and others for which administration of a 5-HT1D ligand is indicated. Also they could be used diagnostically, for example, to identify these receptors and to screen drug candidates.
According to one aspect of the present invention there are provided compositions, either for use as reagents, for example in the identification of 5-HT1D receptors or receptor ligands, or for pharmaceutical use to treat conditions where stimulation of the 5-HT1D receptor is indicated, containing the compounds of Formula I: 
wherein:
R1 is selected from the group consisting of a group of Formula II: 
xe2x80x83H, halo, OH, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-7cycloalkenyl, C3-7cycloalkoxy, C3-7cycloalkylthio, halo-substituted-C1-6alkyl, C1-6alkylthio, C2-7alkanoyl, C2-7alkanoyloxy, nitro, cyano, optionally substituted phenyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted phenyloxy, CH2SO2NR7R8, C(O)R9, OC(O)R9, NR14R15, C(O)NR14R15, SO2NR14R15, CO2R16, NHC(O)R17, NHC(NR16)R17, C(NR19)NR20R21, SCF3, SO2CF3, formyl, CF3 and CF3O;
X is selected from the group consisting of O, S, SO, SO2, NR10 and CR11R12;
- - - - - , in ring A and ring B, represents a single or double bond provided that only one double bond is present in a ring at a time;
R2 is selected from the group consisting of H, OH, C1-6alkyl and C1-6alkoxy;
R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy,
C1-6alkylthio and optionally substituted benzyloxy;
R4 is selected from the group consisting of H and C1-4alkyl;
R5 is selected from the group consisting of H, OH, C1-6alkyl and C1-6alkoxy;
R6 is selected from the group consisting of H, OH, C1-6alkoxy or null, provided that when R6 is selected from the group consisting of H, OH and C1-6alkoxy, - - - - - represents a single bond in ring A and when R6 is null, - - - - - represents a double bond in ring A;
R7 and R3 are independently selected from the group consisting of H and C1-6alkyl;
R9 is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, optionally substituted furanyl and optionally substituted naphthyl;
R10 is selected from the group consisting of H, C1-6alkyl, optionally substituted benzyl, C(O)NHR13, SO2NHR13 and C(S)NHR13;
One of R11 and R12 is selected from the group consisting of H, C1-6alkyl and optionally substituted benzyl and the other is H;
R13 is selected from the group consisting of H, C1-6alkyl, optionally substituted phenyl, optionally substituted benzyl and optionally substituted naphthyl;
R14, R15 and R16 are independently selected from the group consisting of H,
C1-6alkyl and phenyl or R14 and R15 may form an alkylene bridge, xe2x80x94(CH2)nxe2x80x94,
where n=3-6, to form, together with the nitrogen to which they are attached a 4- to 7- membered ring;
R17 is selected from the group consisting of H, C1-6alkyl, C1-6alkoxy, phenyl, phenoxy, NH2, alkylamino, dialkylamino, benzyl and benzyloxy;
R18 is selected from the group consisting of H and C1-6alkyl;
R19 is selected from the group consisting of H and C1-6alkyl;
R20 and R21 are independently selected from the group consisting of H and C1-6alkyl or one of R20 and R21, together with R19, forms an alkylene bridge, xe2x80x94(CH2)nxe2x80x94, where n=2 or 3, connecting the nitrogen atoms to which they are attached;
n is selected from the group consisting of an integer of from 1-3; and
Z is selected from the group consisting of C and N, provided that when Z is N, - - - - - represents a single bond in ring B.
It is another aspect of the present invention to provide a method effective to treat medical conditions for which stimulation of the 5-HT1D receptor is indicated, such as to treat migraine.
According to another aspect of the invention, there are provided compounds of Formula III and a salt, solvate or hydrate thereof: 
wherein:
R1 is a group of Formula II: 
xe2x80x83X is selected from the group consisting of O, S, SO, SO2, NR10 and CR11R12;
- - - - - , in ring A and ring B, represents a single or double bond provided that only one double bond is present in a ring at a time;
R2 is selected from the group consisting of H, OH, C1-6alkyl and C1-6alkoxy;
R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio and optionally substituted benzyloxy;
R4 is selected from the group consisting of H and C1-4alkyl;
R5 is selected from the group consisting of H, OH, C1-6alkyl and C1-6alkoxy;
R6 is selected from the group consisting of H, OH, C1-6alkoxy or null, provided that when R6 is selected from the group consisting of H, OH and C1-6alkoxy, - - - - - represents a single bond in ring A and when R6 is null, - - - - - represents a double bond in ring A;
R10 is selected from the group consisting of H, C1-6alkyl, optionally substituted benzyl, C(O)NHR13, SO2NHR13 and C(S)NHR13;
One of R11 and R12 is selected from the group consisting of H, C1-6alkyl and optionally substituted benzyl and the other is H;
R13 is selected from the group consisting of H, C1-6alkyl, optionally substituted phenyl, optionally substituted benzyl and optionally substituted naphthyl;
n is selected from the group consisting of an integer of from 1-3;
Z is selected from the group consisting of C and N, provided that when Z is N, represents a single bond in ring B.
It is an aspect of the present invention to provide a compound that binds to the 5-HT1D receptor.
It is another aspect of the present invention to provide compounds which bind selectively to the 5-HT1D receptor, relative particularly to the 5-HT1B receptor.
These and other aspects of the present invention are described in greater detail hereinbelow.
The term xe2x80x9cC1-6alkylxe2x80x9d as used herein means straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
The term xe2x80x9cC1-6alkoxyxe2x80x9d as used herein means straight and branched chain alkoxy radicals containing from one to six carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
The term xe2x80x9cC2-6alkenylxe2x80x9d as used herein means straight and branched chain alkenyl radicals containing from two to six carbon atoms and includes ethenyl, 1-propenyl, 1-butenyl and the like.
The term xe2x80x9cC2-6alkynylxe2x80x9d as used herein means straight and branched chain alkynyl radicals containing from two to six carbon atoms and includes 1-propynyl (propargyl), 1-butynyl and the like.
The term xe2x80x9cC3-7cycloalkylxe2x80x9d as used herein means saturated carbocyclic radicals containing from 3-7 carbon atoms and includes cyclopropyl, cyclohexyl and the like.
The term xe2x80x9cC3-7cycoalkyloxyxe2x80x9d as used herein means saturated carbocyclo-oxy radicals containing from 3-7 carbon atoms and includes cyclopropyloxy, cyclohexyloxy and the like.
The term xe2x80x9cC3-7cycloalkylthioxe2x80x9d as used herein means saturated carbocycloalkylthio radicals containing from 3-7 carbon atoms and includes cyclopropylthio, cyclohexylthio and the like.
The term xe2x80x9cC2-7alkanoylxe2x80x9d as used herein means straight and branched chain alkanoyl radicals (xe2x80x94C(O)C1-6alkyl) containing from 2-7 atoms and includes acetyl, propionyl, butyryl and the like.
The term xe2x80x9cC2-7alkanoyloxyxe2x80x9d as used herein means straight and branched chain alkanoyloxy radicals (xe2x80x94OC(O)C1-6alkyl) containing from 2-7 carbon atoms and includes acetoxy, propionyloxy, butyryloxy and the like.
The term xe2x80x9cC4-7cycloalkenylxe2x80x9d as used herein means carbocyclic radicals containing from 4-7 carbon atoms and one unit of unsaturation and includes cyclopent-1-enyl, cyclohexenyl and the like.
The term xe2x80x9coptionally substituted phenylxe2x80x9d as used herein means an unsubstituted phenyl radical or phenyl radicals substituted with 1-3 substituents independently selected from halo, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, CF3 and CF3O.
The term xe2x80x9coptionally substituted phenoxyxe2x80x9d as used herein means an unsubstituted phenoxy radical or a phenoxy radical substituted with 1-3 substituents independently selected from halo, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, CF3 and CF3O.
The term xe2x80x9coptionally substituted thienylxe2x80x9d as used herein means an unsubstituted thienyl radical or a thienyl radical substituted with 1-2 substituents independently selected from halo, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, CF3 and CF3O.
The term xe2x80x9coptionally substituted furanylxe2x80x9d as used herein means an unsubstituted furanyl radical or a furanyl radical substituted with 1-2 substituents independently selected from halo, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, CF3 and CF3O.
The term xe2x80x9coptionally substituted pyridylxe2x80x9d as used herein means an unsubstituted pyridyl radical or a pyridyl radical substituted with 1-2 substituents independently selected from halo, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, CF3 and CF3O.
The term xe2x80x9coptionally substituted naphthylxe2x80x9d as used herein means an unsubstituted naphthyl radical or a naphthyl radical substituted with 1-4 substituents independently selected from halo, OH, C1-6alkyl, C1-6alkoxy, C1-4alkylthio, CF3 and CF3O.
The term xe2x80x9coptionally substituted benzylxe2x80x9d as used herein means an unsubstituted benzyl radical or a benzyl radical substituted on the phenyl ring with 1-3 substituents independently selected from halo, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, CF3 and CF3O.
The term xe2x80x9coptionally substituted benzyloxyxe2x80x9d as used herein means an unsubstituted benzyloxy radical or a benzyloxy radical substituted on the phenyl ring with 1-3 substituents independently selected from halo, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, CF3 and CF3O.
The term xe2x80x9calkylaminoxe2x80x9d as used herein means an amino radical which is monosubstituted with a C1-6alkyl group.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein means an amino radical which is disubstituted with C1-6alkyl groups, wherein each alkyl group may be the same or different.
The term halo as used herein means halogen and includes fluoro, chloro, bromo, iodo and the like, in both radioactive and non radioactive forms.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients.
A xe2x80x9cpharmaceutically acceptable acid addition saltxe2x80x9d is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formulae I and III or any of their intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formulae I and III are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formulae I and III for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. It should be noted that compounds of Formulae I and III, wherein Z is N, are not stable in the presence of strong acid (for example 1N HCl), therefore when preparing acid addition salts of such compounds, care must be taken to select an appropriately mild acid, for example citric acid.
A xe2x80x9cpharmaceutically acceptable basic addition saltxe2x80x9d is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formulae I and III or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. Those skilled in the art will appreciate that the selection of the appropriate salt may be important so that any ester functionality in the molecule is not hydrolyzed.
xe2x80x9cSolvatexe2x80x9d means a compound of Formula I or III or the pharmaceutically acceptable salt of a compound of Formula I or III wherein molecules of a suitable solvent are incorporated in a crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.
The term xe2x80x9cstereoisomersxe2x80x9d is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
The term xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d means an amount of the compound which is effective in treating the named disorder or condition.
The term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.
The present invention includes within its scope prodrugs of the compounds of Formulae I and III. In general, such prodrugs will be functional derivatives of a compound of Formula I or III which are readily convertible in vivo into the required compound of Formula I or III. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d ed. H. Bundgaard, Elsevier, 1985.
Compounds of Formula I and III bind selectively (for example with 10-fold selectivity) to the to the serotonin 5-HT1D receptor, relative, particularly, to the serotonin 5-HT1B receptor, as judged by in vitro binding affinities using, for example, the assay exemplified herein. Preferred compounds are those which bind with at least 10-fold selectivity to the 5-HT1D receptor, relative to the 5-HT1B receptor. More preferred compounds are those which bind with at least 40-fold selectivity to the 5-HT1D receptor, relative to the 5-HT1B receptor.
The present invention embodies compositions, either for use as reagents, for example in the identification of 5-HT1D receptors or receptor ligands, or for pharmaceutical use to treat conditions where stimulation of the 5-HT1D receptor is indicated, containing the compounds of Formula I. In further embodiments, the composition comprises a compound of Formula I wherein R1 is selected from a group of Formula II: 
H, halo, OH, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C4-7cycloalkenyl, C3-7cycloalkoxy, C3-7cycloalkylthio, halo-substituted-C1-6alkyl, C1-6alkylthio, C2-7alkanoyl, C2-7alkanoyloxy, nitro, cyano, optionally substituted phenyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted phenyloxy, CH2SO2NR7R8, C(O)R9, OC(O)R9, NR14R15, C(O)NR14R15, SO2NR14R15, CO2R16, NHC(O)R17, NHC(NR18)R17, C(NR19)NR20R21, SCF3, SO2CF3, formyl, CF3 and CF3O. In specific embodiments, R1 is selected from a group of Formula II, H, halo, C1-6alkyl, C1-6alkoxy, optionally substituted thienyl, optionally substituted furanyl, C(O)Ph, C3-7cycloalkoxy, CF3 and CF3O. In more specific embodiments, R1 is selected from a group of Formula II, bromo, fluoro, methyl, isopropyl, methoxy, unsubstituted thienyl, unsubstituted furanyl, C(O)Ph and cyclohexyloxy. In the most specific embodiments, R1 is selected from methyl, isopropyl, unsubstituted thienyl, unsubstituted furanyl and a group of Formula II selected from tetrahydro-2H-pyran-4-ol, cyclohexen-1-yl and 5,6-dihydro-2H-thiopyran-4-yl. When R1 is a group of Formula II, X is selected from O, S, SO, SO2, NR10 and CR11R12, wherein R10 is selected from of H, C1-6alkyl, optionally substituted benzyl, C(O)NHR13, SO2NHR13 and C(S)NHR13 and one of R11 and R12 is selected from H, C1-6alkyl and optionally substituted benzyl and the other is H. In specific embodiments, X is selected from O, S, SO, SO2, NR10 and CR11 R12, wherein R10 is selected from H, C1-4alkyl and optionally substituted benzyl, and one of R11 and R12 is selected from H, C1-4alkyl and optionally substituted benzyl and the other is H. In more specific embodiments X is selected from O, S, NH, NMethyl, NEthyl, NBenzyl, CHMethyl, CHBenzyl and CH2. Most specifically, X is selected from O, S and CH2. When R10 is selected from C(O)NHR13, SO2NHR13 and C(S)NHR13, R13 is selected from the group consisting of H, C1-6alkyl, optionally substituted phenyl, optionally substituted benzyl and optionally substituted naphthyl. Specifically, R13 is selected from the group consisting of H, C1-4alkyl, optionally substituted phenyl and optionally substituted benzyl. More specifically, R13 is selected from the group consisting of H, C1-4alkyl, unsubstituted phenyl and unsubstituted benzyl. Also within the group of Formula II, R5 is selected from H, OH, C1-6alkyl and C1-6alkoxy. In specific embodiments, R5 is selected from H, OH, C1-4alkyl and C1-4alkoxy. In more specific embodiments, R5 is H, OH, methyl and methoxy. In the most specific embodiment, R5 is H. Further, in the group of Formula II, R6 is selected from H, OH, C1-6alkoxy or null, provided that when R6 is selected from H, OH and C1-6alkoxy, - - - - - represents a single bond in ring A and when R6 is null, - - - - - represents a double bond in ring A. When - - - - - represents a double bond, there is only one double bond present in the ring at a time. In specific embodiments, R6 is selected from H, OH, C1-4alkoxy and null. More specifically, R6 is selected from H, OH, methoxy and null. Most specifically, R6 is selected from H and null.
In further embodiments, when the composition comprises a compound of Formula I, wherein R1 is selected from CH2SO2NR7R8, C(O)R9 and OC(O)R9, R7 and R8 are independently selected from the group consisting of H and C1-6alkyl and R9 is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, optionally substituted furanyl and optionally substituted naphthyl. In specific embodiments, R7 and R8 are independently selected from the group consisting of H and C1-4alkyl and R9 is selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl. More specifically, R7 and R8 are independently selected from the group consisting of H and methyl and R9 is selected from the group consisting of unsubstituted phenyl and unsubstituted naphthyl.
In other embodiments, when the composition comprises a compound of Formula 1, wherein R1 is selected from NR14R15, C(O)NR14R15, SO2NR14R15, CH2SO2NR14R15 and CO2R16, R14, R15 and R16 are independently selected from the group consisting of H, C1-6alkyl and phenyl or R14 and R15 may form an alkylene chain, xe2x80x94(CH2)nxe2x80x94, where n=3-6, to form, together with the nitrogen to which they are attached a 4- to 7-membered ring. In specific embodiments, R14, R15 and R16 are independently selected from the group consisting of H and C1-4alkyl or R14 and R15 may form an alkylene chain, xe2x80x94(CH2)nxe2x80x94, where n=4-5, to form, together with the nitrogen to which they are attached a 5- to 6-membered ring. In more specific embodiments, R14, R15 and R16 are independently selected from the group consisting of H and methyl or R14 and R15 may form an alkylene chain, xe2x80x94(CH2)nxe2x80x94, where n=4-5, to form, together with the nitrogen to which they are attached a 5- to 6-membered ring.
Further embodiments include compositions comprising a compound of Formula I, wherein R1 is selected from NHC(O)R17, NHC(NR18)R17 and R17 is selected from H, C1-6alkyl, C1-6alkoxy, phenyl, phenoxy, NH2, alkylamino, dialkylamino, benzyl and benzyloxy and R18 is selected from H and C1-6alkyl. In specific embodiments, R17 is selected from C1-4alkyl, C1-4alkoxy, phenyl, phenoxy, NH2, alkylamino, dialkylamino, benzyl and benzyloxy and R18 is selected from H and C1-4alkyl. In more specific embodiments, R17 is selected from methyl, methoxy, phenyl, phenoxy, NH2, alkylamino, dialkylamino, benzyl and benzyloxy and R18 is selected from the group consisting of H and methyl. Further, when R1 is C(NR19)NR20R21 in compounds of Formula I, R19 is selected from the group consisting of H and C1-6alkyl and R20 and R21 are independently selected from H and C1-6alkyl or one of R20 and R21, together with R19, forms an alkylene chain, xe2x80x94(CH2)nxe2x80x94, where n=2 or 3, bridging the nitrogen atoms to which they are attached. In specific embodiments, R19 is selected from the group consisting of H and C1-4alkyl and R20 and R21 are independently selected from the group consisting of H and C1-4alkyl or one of R20 and R21, together with R19, forms an alkylene chain, xe2x80x94(CH2)nxe2x80x94, where n=2 or 3, bridging the nitrogen atoms to which they are attached. In more specific embodiments, R19 is selected from the group consisting of H and methyl and R20 and R21 are independently selected from the group consisting of H and methyl or one of R20 and R21, together with R19, forms an alkylene chain, xe2x80x94(CH2)nxe2x80x94, where n=3, bridging the nitrogen atoms to which they are attached.
In another embodiment of the invention, the composition comprises a compound of Formula I wherein R2 is selected from the group consisting of H, OH, C1-6alkyl and C1-6alkoxy and R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio and optionally substituted benzyloxy. In specific embodiments, R2 is selected from the group consisting of H, and C1-4alkyl and R3 is selected from the group consisting of H, C1-4alkyl, C1-4alkoxy and C1-4alkylthio. In more specific embodiments, R2 is selected from H and methyl and R3 is H.
In a further embodiment of the invention, the composition comprises a compound of Formula I wherein R4 is selected from H and C1-4alkyl. In specific embodiments, R4 is H and methyl. In preferred embodiments, R4 is H.
In another of its embodiments, the invention includes compositions comprising a compound of Formula I wherein where n is selected from the group consisting of an integer of from 1-3. Specifically, n is selected from 1 and 2. More specifically, n is 1.
In further embodiments of the invention, the composition comprises a compound of Formula I wherein Z is selected from the group consisting of C and N and - - - - - represents a single or double bond, provided that when Z is N, - - - - - represents a single bond in ring B. In preferred embodiments, Z is C and - - - - - represents either a single or double bond in ring B. In more preferred embodiments, - - - - - represents a double bond and (when n is 1) this double bond is located in the 6,7-position of the indolizine ring system.
Specifically, the composition comprises a compound of Formula I selected from:
5-Fluoro-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Methoxy-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Methyl-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Isopropyl-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Bromo-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Cyclohexyloxy-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(2-Thienyl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Isopropyl-3-[(8a,R,S)-6-methyl-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
1-{[3-(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indol-5-yl}cyclohexanol;
1-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}-N-methyl-4-azacyclohexanol;
4-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}tetrahydro-2H-pyran4-ol;
5-(5,6-Dihydro-2H-pyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-pyran-4-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Fluoro-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer I;
5-Fluoro-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer II;
5-Isopropyl-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer I;
5-Isopropyl-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer II;
5-Methoxy-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer I;
5-Methoxy-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer II;
5-(Tetrahydropyran-4-yl)-[(7-R,S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole;
5-Bromo-3-[(7-R,S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole;
3-[(6-R,S)-1,4-Diaza[4.3.0]bicyclonon-4-yl]-1H-indole;
3-[(6-R,S)-1,4-Diaza[4.4.0]bicyclodecan-4-yl]-1H-indole;
5-(Cyclohexen-1-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(Cyclohexen-1-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-thiopyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-thiopyran-4-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole;
3-[(7-R,S)(8a-R,S)-Octahydro-7-indolizinyl]-5-(2-thienyl)-1H-indole; {3-[(7R or 7S)(8a-R,S)-Octahydro-7-indolizinyl]1H-indol-5-yl}phenylmethanone, Isomer I;
{3-[(7R or 7S)(8a-R,S)-Octahydro-7-indolizinyl]1H-indol-5-yl}phenylmethanone, Isomer II; and
{3-[(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}phenylmethanone.
In more specific embodiments of the invention, the composition comprises a compound of Formula I selected from:
5-Methoxy-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Methyl-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Isopropyl-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Bromo-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Cyclohexyloxy-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(2-Thienyl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Isopropyl-3-[(8a,R,S)-6-methyl-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
1-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}cyclohexanol;
4-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}tetrahydro-2H-pyran-4-ol;
5-(5,6-Dihydro-2H-pyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-pyran-4-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Isopropyl-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer I;
5-Isopropyl-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer II;
5-(Tetrahydropyran-4-yl)-[(7-R,S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole;
5-(Cyclohexen-1-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(Cyclohexen-1-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-thiopyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-thiopyran-4-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole; and
3-[(7-R,S)(8a-R,S)-Octahydro-7-indolizinyl]-5-(2-thienyl)-1H-indole.
In even more specific embodiments of the invention, the composition comprises a compound of Formula I selected from:
5-Methoxy-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Methyl-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Isopropyl-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Isopropyl-3-[(8a,R,S)-6-methyl-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
1-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}cyclohexanol;
4-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}tetrahydro-2H-pyran-4-ol;
5-Isopropyl-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer I;
5-Isopropyl-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer II;
5-(Cyclohexen-1-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-thiopyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole; and
3-[(7-R,S)(8a-R,S)-Octahydro-7-indolizinyl]-5-(2-thienyl)-1H-indole.
In the most specific embodiments of the invention, the composition comprises a compound of Formula I selected from:
5-Methyl-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-isopropyl-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Isopropyl-3-[(8a,R,S)-6-methyl-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-Isopropyl-3-[(7R or 7S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole, Isomer II; and
3-[(7-R,S)(8a-R,S)-Octahydro-7-indolizinyl]-5-(2-thienyl)-1H-indole.
The present invention also provides compounds of Formula III. In embodiments of the invention, compounds of Formula III include those in which R1 is a group of Formula II: 
Within the group of Formula II, X is selected from O, S, SO, SO2, NR10 and C11R12, wherein R10 is selected from H, C1-6alkyl, optionally substituted benzyl, C(O)NHR13, SO2NHR13 and C(S)NHR13; and one of R11 and R12 is selected from H, C1-6alkyl and optionally substituted benzyl and the other is H. In specific embodiments, X is selected from O, S, SO, SO2, NR10 and CR11R12, wherein R10 is selected from H, C1-4alkyl and optionally substituted benzyl, and one of R11 and R12 is selected from H, C1-4alkyl and optionally substituted benzyl and the other is H. In more specific embodiments X is selected from O, S, NH, NMethyl, NEthyl, NBenzyl, CHMethyl, CHBenzyl and CH2. Most specifically, X is selected from O, S and CH2. When R10 is selected from C(O)NHR13, SO2NHR13 and C(S)NHR13, R13 is selected from the group consisting of H, C1-6alkyl, optionally substituted phenyl, optionally substituted benzyl and optionally substituted naphthyl. Specifically, R13 is selected from the group consisting of H, C1-4alkyl, optionally substituted phenyl and optionally substituted benzyl. More specifically, R13 is selected from the group consisting of H, C1-4alkyl, unsubstituted phenyl and unsubstituted benzyl. Also within the group of Formula II, R5 is selected from H, OH, C1-6alkyl and C1-6alkoxy. In specific embodiments, R5 is selected from H, OH, C1-4alkyl and C1-4alkoxy. In more specific embodiments, R5 is H, OH, methyl and methoxy. In the most specific embodiment, R5 is H. Further, in the group of Formula II, R6 is selected from H, OH, C1-6alkoxy or null, provided that when R6 is selected from H, OH and C1-6alkoxy, - - - - - represents a single bond in ring A and when R5 is null, - - - - - represents a double bond in ring A. When - - - - - represents a double bond, there is only one double bond present in the ring at a time. In specific embodiments, R6 is selected from H, OH, C1-4alkoxy and null. More specifically, R6 is selected from H, OH, methoxy and null. Most specifically, R6 is selected from H and null.
In further embodiments of the invention, compounds of Formula III include those in which R2 is selected from the group consisting of H, OH, C1-6alkyl and C1-6alkoxy and R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, C1-6alkylthio and optionally substituted benzyloxy. In specific embodiments, R2 is selected from the group consisting of H, and C1-4alkyl and R3 is selected from the group consisting of H, C1-4alkyl, C1-4alkoxy and C1-4alkylthio. In more specific embodiments, R2 is selected from H and methyl and R3 is H.
In another embodiment of the invention, compounds of Formula III include those in which R4 is selected from H and C1-4alkyl. In specific embodiments R4 is selected from H and methyl. In preferred embodiments, R4 is H.
In another of its embodiments, the invention includes compounds of Formula III where n is selected from the group consisting of an integer of from 1-3. Specifically, n is selected from 1 and 2. More specifically, n is 1.
In further embodiments of the invention, compounds of Formula III include those in which Z is selected from the group consisting of C and N and - - - - - represents a single or double bond, provided that when Z is N, - - - - - represents a single bond in ring B. In preferred embodiments, Z is C and - - - - - represents either a single or double bond in ring B. In more preferred embodiments, - - - - - represents a double bond and (when n is 1) this double bond is located in the 6,7-position of the indolizine ring system.
Specific compounds of Formula III include:
1-{[3-(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indol-5-yl}-N-methyl-4-azacyclohexanol;
4-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}tetrahydro-2H-pyran-4-ol;
1-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}cyclohexanol;
5-(5,6-Dihydro-2H-pyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-pyran-4-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(Tetrahydropyran-4-yl)-[(7-R,S)(8a-R,S)-octahydro-7-indolizinyl]-1H-indole;
5-(Cyclohexen-1-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(Cyclohexen-1-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-thiopyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-thiopyran-4-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole; and
{3-[(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}phenylmethanone.
In more specific embodiments of the invention, the compounds of Formula III include:
4-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}tetrahydro-2H-pyran-4-ol;
1-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}cyclohexanol;
5-(5,6-Dihydro-2H-pyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(5,6-Dihydro-2H-pyran-4-yl)-3-[(8a-R,S)-1,2,3,5,6,8a-hexahydro-7-indolizinyl]-1H-indole;
5-(Cyclohexen-1-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole; and
5-(5,6-Dihydro-2H-thiopyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole.
In even more specific embodiments of the invention, the compounds of Formula III include:
4-{[3-(8a-R,S)-1,2,3,5,8,8a-Hexahydro-7-indolizinyl]-1H-indol-5-yl}tetrahydro-2H-pyran-4-ol;
5-(Cyclohexen-1-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole; and
5-(5,6-Dihydro-2H-thiopyran-4-yl)-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole.
All of the compounds of Formulae I and III have at least one asymmetric centre. Where the compounds according to the invention have one asymmetric centre they may exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Acid addition salts of the compounds of Formulae I and III are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids (not recommended when Z=N) and organic acids e.g. succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques in which an aqueous solution of the given salt is treated with a solution of base or acid, e.g. sodium carbonate, potassium hydroxide or hydrochloric acid (provided that caution is taken when Z is N) or, to liberate the neutral compound which is then extracted into an appropriate solvent, such as ether. The neutral compound is then separated from the aqueous portion, dried, and treated with the requisite acid or base to give the desired salt.
Also included within the scope of the invention are solvates of the invention. The formation of the solvate will vary depending on the compound and solvent used. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
Prodrugs of compounds of Formula I or III may be conventional esters with available hydroxyl (or thiol) or carboxyl groups. For example, when one of R1-R3 or R5-R6 is OH in a compound of Formula I or III, it may be acylated using an activated acid in the presense of a base and, optionally, in inert solvent (e.g. an acid chloride in pyridine). Also, when R1 is CO2R16 in a compound of Formula I, wherein R16 is H, an ester may be formed by activation of the hydroxyl group of the acid and treatment with the appropriate alcohol in the presence of a base in an inert solvent. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters. Prodrugs of compounds of Formulae I and III may also be formed by functional derivatization of substituents containing an acidic NH group, for example, compounds of Formula I or III where, R10 is C(O)NHR13, SO2NHR13 and C(S)NHR13 or compounds of Formula I, where R1 is C(O)NR14R15, SO2NR14R15, NHC(NR18)R17 or C(NR19)NR20R21 and one of the groups attached to a nitrogen is H. Some common prodrugs for amides, imides and other NH-acidic compounds are N-Mannich bases, N-hydroxymethyl derivatives, N-acyloxyalkyl derivatives, and N-acyl derivatives.
In accordance with another of its aspects, the compounds of the present invention can be prepared by processes analogous to those established in the art. For example, compounds of Formulae I and III, wherein R4 is C1-4alkyl, may be prepared from another compound of Formula I or III, wherein R4 is H, by alkylation of the indole nitrogen using standard conditions. Such conditions may involve treating the NH compound with a strong base such as sodium hydride or sodium hexamethyldisilazide at low temperatures, for example xe2x88x9278-0xc2x0 C., and in an inert solvent such as tetrahydrofuran, followed by the addition of a reagent of the formula R4xe2x80x94Y, wherein R4 is C1-4alkyl and Y is a suitable leaving group such as halo (for example bromo).
Compounds of Formula Ia and Iaxe2x80x2, wherein R1-R3 and n are as defined in Formula I, R4 is H, Z is C and - - - - - represents a double bond, may be prepared, as shown in Scheme 1, by condensing a compound of Formula A, wherein R1 is as defined in Formula I, with a reagent of Formula B, wherein R2, R3 and n are as defined in Formula I, either in acidic or basic conditions in a suitable solvent, to provide compounds of Formula Ia and Iaxe2x80x2, wherein R1-R3 and n are as defined in Formula I, R4 is H, Z is C and - - - - - represents a double bond. Suitable basic conditions include organic amines such as pyrrolidine or triethylamine in solvents such as methanol, ethanol and the like. Preferred basic conditions are pyrrolidine in ethanol at a refluxing temperature. Suitable acidic conditions include, for example, trifluoracetic acid in acetic acid at a temperature in the range of 90-120xc2x0 C., preferably at around 110xc2x0 C. When the reaction of compound A with compound B is carried out in basic conditions, typically the regioisomer corresponding to Ia is the sole product formed. Under acidic conditions, both regioisomeric alkenes, Ia and Iaxe2x80x2, may be isolated, the ratio of which will vary depending on reaction conditions and the identity and position of R2. The Compounds of Formula Ia and Iaxe2x80x2, wherein R1-R3 and n are as defined in Formula I, R4 is H, Z is C and - - - - - represents a double bond, may be reduced using standard hydrogenation conditions, ionic hydrogenation conditions or using metal hydride reducing reagents to provide compounds of Formula Ib, wherein R1-R3 and n are as defined in Formula I, R4 is H, Z is C and - - - - - represents a single bond as shown in Scheme 1. Preferred is reduction by hydrogenation, using a suitable catalyst such as palladium or platinum on carbon in methanol or ethanol at room temperature, or reduction by ionic hydrogenation using a mixture if a trialkylsilane, preferably triethylsilane, and an acid such as trifluoracetic acid, in a nonpolar solvent such as dichloromethane at room temperature. 
Compounds of Formula Ic, wherein R1-R3 and n are as defined in Formula I, R4 is H, Z is N and - - - - - is a single bond, may be prepared as shown in Scheme 2. A compound of Formula C or a compound of Formula D, wherein R1 is as defined in Formula I, and PG is a suitable protecting group such as acetate or tosyl, may be reacted with a bicyclic piperazine of Formula E, wherein R2, R3 and n are as defined in Formula I, in the presence of a catalytic amount of an acid, such as p-toluenesulfonic acid or camphorsulfonic acid, in an inert solvent such as toluene or benzene, at temperatures in the range of 25-120xc2x0 C., preferably at refluxing temperatures. Removal of the protecting group under standard conditions, for example, an alkali base such as sodium hydroxide in a polar solvent such as methanol at temperatures in the range of 20-100xc2x0 C., suitably 50-80xc2x0 C., for removal of an acetate group, provides compounds of Formula Ic, wherein R1-R3 and n are as defined in Formula I, R4 is H, Z is N and - - - - - is a single bond. 
Compounds of Formula A, wherein R1 is as defined in Formula I, are either commercially available or can be prepared using standard procedures. For example, compounds of Formula A may be prepared using the well known Fischer indolization method (see March, J, Advanced Organic Chemistry, John Wiley and Sons, 1985, p. 1032-1033, and references found therein) or using the procedure shown in Scheme 3. 4-Substituted anilines of Formula F, wherein R1 is as defined in Formula I, can be treated with reagents of Formula G, in the presence of a base such as sodium bicarbonate or potassium carbonate in an alcoholic solvent at temperatures in the range of 60-100xc2x0 C., to provide intermediates of Formula H. Preferred conditions are sodium bicarbonate in ethanol at.around 80xc2x0 C. Intermediates of Formula H can be cyclized in the presence of reagents of Formula J, wherein R is, for example, methyl or trifluoromethyl (which is preferred) at temperatures in the range of 60-100xc2x0 C., to provide indoles of Formula K. The preferred conditions are trifluoroacetic anhydride and trifluoroacetic acid at refluxing temperatures. Finally, compounds of Formula K can be treated under standard deprotection conditions, for example alkali hydroxides in an alcoholic solvent, to provide indoles of Formula A, wherein R1 is as defined in Formula I. Preferred conditions for this reaction are potassium hydroxide in ethanol at room temperature. The reagents of Formula F and G, are either commercially available or can be prepared using processes analogous to those established in the art. 
Compounds of Formula A, wherein R1 is specifically a group of Formula II, can be prepared, as shown below in Scheme 4. An indole reagent of Formula L, wherein Y is a suitable leaving group such as halo, (preferably bromo or iodo), and PG is a suitable protecting group, such a trialkylsilyl, arylsulfonyl or alkylsulfonyl group, preferably t-butyldimethylsilyl, can be treated with strong base, such as an alkyllithium, preferably t-butyllithium, followed by the addition of a ketone of Formula M, wherein X and R5 are as defined in Formula I, to provide compounds of Formula N, wherein R5, X and PG are as defined above. This reaction is performed in inert solvents, such as ether or tetrahydrofuran, at temperatures ranging from xe2x88x92100 to 0xc2x0 C. Preferred conditions are tetrahydrofuran at xe2x88x9278xc2x0 C. It should be noted that if two equivalents of a strong base (for example, potassium hydride followed by t-butyllithium) are used in this reaction, it may not be necessary to protect the indole nitrogen. Removal of the protecting group on the indole nitrogen may be performed using standard procedures. For example, when PG is a trialkylsilyl group such as t-butyldimethylsilyl, compounds of Formula N are suitably deprotected using tetrabutylammonium fluoride in THF at room temperature, to provide compounds of Formula A(i), wherein X and R5 are as defined in Formula I. Compounds of Formula A(i) may be dehydrated under standard conditions, for example, formation of the mesylate and elimination under basic conditions or in the presence of an acid such as trifluoroacetic acid in an inert solvent such as tetrahydrofuran, to provide compounds of Formula A(ii), wherein X and R5 are as defined in Formula I, as shown in Scheme 4. It should be noted that when R5 is other than H, a mixture of regioisomeric alkenes may be obtained. Compounds of Formula A (ii) may be reduced using standard hydrogenation conditions or using metal hydride reducing reagents to provide compounds of Formula A(iii), wherein X and R5 are as defined in Formula I, as shown in Scheme 4. Preferred is reduction by hydrogenation, using a suitable catalyst such as palladium or platinum on carbon in methanol or ethanol at room temperature. 
An alternate route to the preparation of compounds of Formula A(ii) is shown in Scheme 5. An indole of Formula L, wherein Y is a suitable leaving group such as halo or triflate (preferably bromo) and PG is an appropriate protecting group, such as acetate, may be coupled with with a vinyl trialkylstannane of, for example, Formula P or Q, wherein R5 and X are as defined in Formula I, under standard metal catalyzed-cross coupling condition. It will be appreciated that other metal coupling groups could be used in place of the vinyl stannane, for example, a vinyl boronic acid, chloro zinc and the like. Suitable coupling conditions include refluxing the indole and cyclic metal reagent in an inert solvent, such as dimethylformamide, toluene or tetrahydrofuran, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine) palladium (0). Removal of the protecting group using standard conditions, for example sodium hydroxide in methanol to remove an acetate group, provides compounds of Formula A(ii) (as possible regioisomeric alkenes), wherein R5 and X are as defined in Formula I. This metal-catalyzed cross-coupling procedure could also be applied to the preparation of compounds of Formula A where R1 is vinyl or optionally substituted phenyl, thienyl or furanyl by replacing the reagent of Formula P or Q above with the appropriate metal-containing reagent. It should also be noted that certain R1 groups may be converted to other R1 groups using standard procedures, for example alkylation, acylation, oxidation and reduction. 
The bicyclic piperidinones B and piperizines E, wherein R2, R3 and n are as defined in Formula I, are either commercially available or can be prepared using procedures known in the art. For example, bicyclic piperidinones of Formula B may be prepared according to procedures described in King, F. D., J. Chem. Soc. Perkin Trans. I, 1986:447-453 and bicyclic piperazines of Formula E may be prepared according to procedures described in Power, P. et al., U.S. Pat. No. 5,576,314; Saleh, M. A. et al. J. Org. Chem. 58, 1993:690-695; Urban, F. J. Heterocyclic Chem. 32, 1995:857-861; Bright, G. et al. WO 90/08148; de Costa, B. R. et al. J. Med. Chem. 36, 1993:2311-2320; and Botre, C. et al. J. Med. Chem. 29, 1986:1814-1820. The cyclic stannanes P and Q may be prepared from the corresponding keto compound M using standard chemistries, for example, by reacting the ketone with a base, such as lithium diisopropylamide or triethylamine, and a suitable triflating agent, such as N-phenyltriflimide or triflic anhydride, and converting the resulting triflate to a compound of Formula P or Q by treatment with, for example, a palladium catalyst and a bis(trialkyltin). Alternatively, cyclic stannanes P and Q may be prepared by forming the tosylhydrazone of the corresponsing keto compound M and, using standard Shapiro conditions, trapping the vinyl anion with a suitable reagent like tributyltin chloride.
Compounds of Formula L may be prepared from compounds of Formula O using standard protecting group methodologies. For example, the t-butyldimethylsilyl protecting group may be attached to the indole nitrogen by treating a compound of Formula O, wherein Y is as defined above, with a strong base, such as sodium hexamethyldisilazide, in an inert solvent, such as tetrahydrofuran, at a temperature in the range of xe2x88x9240 to 30xc2x0 C., suitably 25xc2x0 C., followed by the addition of t-butyldimethylsilyl chloride at a reduced temperature, suitably 0xc2x0 C. Compounds of Formulae C and D are known or may be prepared using standard chemistries.
It should be noted that one skilled in the art would realize that the sequence of reactions described above for the preparation of compounds of Formulae I and III can be varied. For example, the group at the indole 3-position may be incorporated into the molecule before the addition of the group at the indole 5-position.
In some cases, the chemistries outlined above may have to be modified, for instance by use of protecting groups, to prevent side reactions due to reactive groups, such as reactive groups attached as substituents. This may be achieved be means of conventional protecting groups, as described in Protective Groups in Organic Chemistry, ed. McOmie, J. F. W. Plenum Press, 1973; and Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
In another embodiment of the invention, the present compounds can be used to distinguish 5-HT1D receptors from other receptor subtypes, for example glutamate or opioid receptors, within a population of receptors, and in particular to distinguish between the 5-HT1D and other 5-HT receptor subtypes. The latter can be achieved by incubating preparations of the 5-HT1D receptor and one of the other 5-HT receptor subtypes (for example 5-HT1B) with a 5-HT1D-selective compound of the invention and then incubating the resulting preparation with a radiolabeled serotonin receptor ligand, for example [3H]-serotonin. The 5-HT1D receptors are then distinguished by determining the difference in membrane-bound activity, with the 5-HT1D receptor exhibiting lesser radioactivity, i.e., lesser [3H]-serotonin binding, than the other 5-HT receptor subtype.
In an aspect of the invention, the compound is provided in labeled form, such as radiolabeled form, e.g. labeled by incorporation within its structure 3H or 14C or by conjugation to 125I. In another aspect of the invention, the compounds in labeled form can be used as competitive ligands to identify 5-HT1D receptor ligands by techniques common in the art. This can be achieved by incubating the receptor or tissue in the presence of a ligand candidate and then incubating the resulting preparation with an equimolar amount of radiolabeled compound of the invention such as [3H]-5-isopropyl-3-[(8a-R,S)-1,2,3,5,8,8a-hexahydro-7-indolizinyl]-1H-indole. 5-HT1D receptor ligands are thus revealed as those that are not significantly displaced by the radiolabeled compound of the present invention. Alternatively, 5-HT1D receptor ligand candidates may be identified by first incubating a radiolabeled form of a compound of the invention then incubating the resulting preparation in the presence of the candidate ligand. A more potent 5-HT1D receptor ligand will, at equimolar concentration, displace the radiolabeled compound of the invention.
A radiolabelled compound of Formula I or III may be prepared using standard methods known in the art. For example, tritium may be incorporated into a compound of Formula I or III using standard techniques, for example by hydrogenation of a suitable precursor to a compound of Formula I using tritium gas and a catalyst. Alternatively, a compound of Formula III wherein R1 is radioactive iodo may be prepared from the corresponding tialkyltin (suitably timethyltin) derivative using standard iodination conditions, such as [125I] sodium iodide in the presence of chloramine-T in a suitable solvent, such as dimethylformamide. The trialkyltin compound may be prepared from the corresponding non-radioactive halo, suitably iodo, compound using standard palladium-catalyzed stannylation conditions, for example hexamethylditin in the presence of tetrakis(triphenylphosphine) palladium (0) in an inert solvent, such as dioxane, and at elevated temperatures, suitably 50-100xc2x0 C.
The present compounds are useful as pharmaceuticals for the treatment of various conditions in which the use of a 5-HT1D ligand is indicated, such as for the treatment of migraine, cluster headache and portal tension, a condition characterized by increased portal vein blood flow and typically associated with cirrhosis of the liver.
For use in medicine, the compounds of the present invention can be administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in an amount effective to stimulate the 5-HT1D receptor.
The compounds of the present invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions will be formulated accordingly.
Compounds of Formula I and their stereoisomers, solvates, hydrates or pharmaceutically acceptable salts for oral administration can be formulated as liquids, for example syrups, suspensions, solutions or emulsions, or as solid forms such as tablets, capsules and lozenges, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutical liquid carrier for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats), preservative (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid), flavouring or colouring agent. A composition in the form of a tablet can be prepared using any, suitable pharmaceutical carrier routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension filled into a soft gelatin capsule.
The compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterisation techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Capsules and cartridges of e.g. gelatin for use in an inhaler or atomizing device may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of for example suppositories or retention enemas, containing a conventional suppository base such as cocoa butter or other glycerides.
A proposed dose of the compounds of the invention for oral, buccal, sublingual or rectal administration to human (about 70 kg body weight) for the treatment of migraine is 0.1 mg to 500 mg, for example 0.5 mg to 100 mg, preferably. 1 mg to 50 mg, of active ingredient per dose which could be administered up to 8 times per day, more usually 1 to 4 times per day. It will be appreciated that it may be necessary to make routine changes to the dosage depending on the age and weight of the patent as well as the severity of the condition to be treated. It should be understood that unless otherwise indicated, the dosages are referred to in terms of the weight of the compound of Formula I calculated as the free base.
The overall daily dosage administered by injection may be in the range of 0.01 mg to 100 mg, preferably between 0.1 mg and 50 mg, e.g., between 1 mg and 25 mg, of a compound of Formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof calculated as the free base, the compound being administered 1 to 4 doses per day.
Aerosol formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d delivered from a pressurized aerosol contains 0.1 to 10 mg of a compound of the invention, and each dose administered via capsules and cartridges in an inhaler contains 0.1 to 50 mg of a compound of the invention. Administration may be several times daily, for example 2 to 8 times, giving for example 1,2 or 3 doses each time. The overall daily dose by inhalation will be similar to that for oral administration.
The compounds of the invention may, if desired, be administered in combination with one or more other therapeutic agents, such as analgesics, anti-inflammatory agents and anti-nauseants.